The induction of senescence in cancer cells is becoming a relevant strategy in tumor treatment. This can be achieved using therapeutic compounds (TIS – therapy induced senescence) or modulation of the immune system. The cytokines IFNy and TNF can induce senescence in tumor cells in vitro and in vivo via TH1 cell treatment in mice (CIS – cytokine induced senescence). Here we show that CIS induction leads to pro-apoptotic features in murine cancer cells. While the majority of CIS cancer cells remain viable, show SA-ß-Gal activity and cease proliferation, the cells accumulate the following features commonly associated with early apoptotic events. Amongst others, the surface localization of negatively charged phospholipids increases under CIS treatment leading to a loss of the original membrane composition. This is accompanied by the increased protein levels of pro-apoptotic proteins (e.g. BID) as well as mitochondrial outer membrane permeabilization (MOMP) and Cytochrome c release. While CIS cancer cells do show an increase in Caspase 3 activity in comparison to non-senescent cancer cells we suspect that the increased levels of the anti-apoptotic protein Bcl-2 in CIS cancer cells counteracts a possible death induction in favor of senescence. Furthermore, we show that CIS acquired vulnerabilities make the cancer cells susceptible to secondary apoptosis (senolysis) by immune mediators. Following senescence with senolysis allowed phagocytosis by macrophages, while non-senescent cancer cells were not cleared. Therefore, senolysis is required for the clearance of senescent tumor cells. Up to date it is not clear whether senescent cancer cells cause harm and should be deleted or whether they are protective by inducing tumor specific immune responses. These findings may allow to answer this Question.

Senescence induces pro-apoptotic features in tumor cells enabling targeted senolysis by type I immune-mediators and subsequent phagocytic clearance